Lactate Deficit in an Alzheimer Disease Mouse Model: The Relationship With Neuronal Damage

Zhang, Mao; Cheng, Xiaofang; Dang, Ruozhi; Zhang, Weiwei; Zhang, Jie; Yao, Zhong-Xiang

doi:10.1093/jnen/nly102

Cited by 83 publications

(59 citation statements)

References 56 publications

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“…Recent studies have shown that the glycolytic enzymes PDK1 and LDHA are primarily expressed within neurons of the frontal cortex and hippocampus of wild-type and transgenic Alzheimer’s disease mice (Harris et al, 2016; Zhang et al, 2018). Interestingly, it was recently shown that the induction of synaptic activity promotes increased neuronal glucose uptake and the expression of glycolytic genes (Bas-Orth et al, 2017; Segarra-Mondejar et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Aerobic Glycolysis Is Required for Spatial Memory Acquisition But Not Memory Retrieval in Mice

Harris

Lone

Lim

et al. 2019

eNeuro

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The consolidation of newly formed memories and their retrieval are energetically demanding processes. Aerobic glycolysis (AG), also known as the Warburg effect, consists of the production of lactate from glucose in the presence of oxygen. The astrocyte neuron lactate shuttle hypothesis posits that astrocytes process glucose by AG to generate lactate, which is used as a fuel source within neurons to maintain synaptic activity. Studies in mice have demonstrated that lactate transport between astrocytes and neurons is required for long-term memory formation, yet the role of lactate production in memory acquisition and retrieval has not previously been explored. Here, we examined the effect of dichloroacetate (DCA), a chemical inhibitor of lactate production, on spatial learning and memory in mice using the Morris water maze (MWM). In vivo hyperpolarized 13 C-pyruvate magnetic resonance spectroscopy revealed decreased conversion of pyruvate to lactate in the mouse brain following DCA administration, concomitant with a reduction in the phosphorylation of pyruvate dehydrogenase. DCA exposure before each training session in the MWM impaired learning, which subsequently resulted in impaired memory during the probe trial. In contrast, mice that underwent training without DCA exposure, but received a single DCA injection before the probe trial exhibited normal memory. Our findings indicate that AG plays a key role during memory acquisition but is less important for the retrieval of established memories. Thus, the activation of AG may be important for learning-dependent synaptic plasticity rather than the activation of signaling cascades required for memory retrieval.

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Section: Discussionmentioning

confidence: 99%

Aerobic Glycolysis Is Required for Spatial Memory Acquisition But Not Memory Retrieval in Mice

Harris

Lone

Lim

et al. 2019

eNeuro

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“…A study in mice carrying mtDNA mutations expressing a proofreading-deficient version of POLG1 reported elevated brain levels of lactate due to an increase in LDHA/LDHB ratio [58]. Additionally, a recent study in a transgenic PS1/APP AD mouse model revealed decreased content of lactate as well as downregulation of LDHA and LDHB in PS1/APP mice, but an increase in LDHA/LDHB ratio postulated to compensate for neuronal lactate deficit and increase lactate production [80]. It has also been shown that increase in LDHA can mediate resistance to Aβ toxicity through upregulation of aerobic glycolysis as a protective mechanism, but it is possible that this effect is present in the prodromal stages of AD [50], while at a later stages of the disease aerobic glycolysis and elevated lactate production may contribute to the cognitive decline associated with AD [28].…”

Section: Discussionmentioning

confidence: 99%

Cellular alterations identified in pluripotent stem cell-derived midbrain spheroids generated from a female patient with progressive external ophthalmoplegia and parkinsonism who carries a novel variation (p.Q811R) in the POLG1 gene

Chumarina

Russ

Azevedo

et al. 2019

acta neuropathol commun

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Variations in the POLG1 gene encoding the catalytic subunit of the mitochondrial DNA polymerase gamma, have recently been associated with Parkinson's disease (PD), especially in patients diagnosed with progressive external ophthalmoplegia (PEO). However, the majority of the studies reporting this association mainly focused on the genetic identification of the variation in POLG1 in PD patient primary cells, and determination of mitochondrial DNA copy number, providing little information about the cellular alterations existing in patient brain cells, in particular dopaminergic neurons. Therefore, through the use of induced pluripotent stem cells (iPSCs), we assessed cellular alterations in novel p.Q811R POLG1 (POLG1 Q811R) variant midbrain dopaminergic neuron-containing spheroids (MDNS) from a female patient who developed early-onset PD, and compared them to cultures derived from a healthy control of the same gender. Both POLG1 variant and control MDNS contained functional midbrain regionalized TH/FOXA2-positive dopaminergic neurons, capable of releasing dopamine. Western blot analysis identified the presence of high molecular weight oligomeric alpha-synuclein in POLG1 Q811R MDNS compared to control cultures. In order to assess POLG1 Q811R-related cellular alterations within the MDNS, we applied massspectrometry based quantitative proteomic analysis. In total, 6749 proteins were identified, with 61 significantly differentially expressed between POLG1 Q811R and control samples. Pro-and anti-inflammatory signaling and pathways involved in energy metabolism were altered. Notably, increased glycolysis in POLG1 Q811R MDNS was suggested by the increase in PFKM and LDHA levels and confirmed using functional analysis of glycolytic rate and oxygen consumption levels. Our results validate the use of iPSCs to assess cellular alterations in relation to PD pathogenesis, in a unique PD patient carrying a novel p.Q811R variation in POLG1, and identify several altered pathways that may be relevant to PD pathogenesis.

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“…Reactive microglia may shift astrocyte signaling from physiological to pathological by increasing production of tumor necrosis factor α (TNFα), thus altering synaptic functions and behavior 57 . Functions lost or altered in reactive astrocytes include neurotransmitter and ion buffering in mouse HD models 58 , communication via gap junctions in the sclerotic hippocampus of patients with epilepsy 59 , phagocytic clearance of dystrophic neurites 60 , and metabolic coupling by glycolysis-derived d-serine 61 and lactate 62 in mouse AD models. The excessive release of GABA by reactive astrocytes in AD 63 and Parkinson's disease 64 Transcriptomics and A1-A2 classification.…”

Section: Impact In Cns Diseasesmentioning

confidence: 99%

Reactive astrocyte nomenclature, definitions, and future directions

et al. 2021

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A full list of affiliations appears at the end of the paper. 'N euroglia' or 'glia' are collective terms describing cells of neuroepithelial (oligodendrocytes, astrocytes, oligodendrocyte progenitor cells, ependymal cells), neural crest (peripheral glia), and myeloid (microglia) origin. Changes in neuroglia associated with diseases of the CNS have been noted, characterized, and conceptualized from the very dawn of neuroglial research. Rudolf Virchow, in a lecture to students and medical doctors in 1858, stressed that 'this very interstitial tissue [that is, neuroglia] of the brain and spinal marrow is one of the most frequent seats of morbid change... ' 1. Changes in the shape, size, or number of glial cells in various pathological contexts have been frequently described by prominent neuroanatomists 2. In particular, hypertrophy of astrocytes was recognized very early as an almost universal sign of CNS pathology: 'the protoplasmic glia elements [that is, astrocytes] are really the elements which exhibit a morbid hypertrophy in pathological conditions' 3. Neuroglial proliferation was thought to accompany CNS lesions, leading to early suggestions that proliferating glia fully replaced damaged neuronal elements 4. Thus, a historical consensus was formed that a change in 'the appearance of neuroglia serves as a delicate indicator of the action of noxious influences upon the central nervous system, ' and the concept of 'reactionary change or gliosis' was accepted 5. While the origin of 'gliosis' is unclear (glia + osis in Greek means 'glial condition or process'; in Latin the suffix-osis acquired the additional meaning of 'disease'; hence 'astrogliosis'

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Lactate Deficit in an Alzheimer Disease Mouse Model: The Relationship With Neuronal Damage

Cited by 83 publications

References 56 publications

Aerobic Glycolysis Is Required for Spatial Memory Acquisition But Not Memory Retrieval in Mice

Aerobic Glycolysis Is Required for Spatial Memory Acquisition But Not Memory Retrieval in Mice

Cellular alterations identified in pluripotent stem cell-derived midbrain spheroids generated from a female patient with progressive external ophthalmoplegia and parkinsonism who carries a novel variation (p.Q811R) in the POLG1 gene

Reactive astrocyte nomenclature, definitions, and future directions

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